Reprogramming of profibrotic macrophages for treatment of bleomycin-induced pulmonary fibrosis
Fenghua Zhang1, Ehab A Ayaub2, Bingbing Wang1
1Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, IN, USA.
Abstract:
Fibrotic diseases cause organ failure that lead to ~45% of all deaths in the United States. Activated macrophages stimulate fibrosis by secreting cytokines that induce fibroblasts to synthesize collagen and extracellular matrix proteins. Although suppression of macrophage-derived cytokine production can halt progression of fibrosis, therapeutic agents that prevent release of these cytokines (e.g., TLR7 agonists) have proven too toxic to administer systemically. Based on the expression of folate receptor β solely on activated myeloid cells, we have created a folate-targeted TLR7 agonist (FA-TLR7-54) that selectively accumulates in profibrotic macrophages and suppresses fibrosis-inducing cytokine production. We demonstrate that FA-TLR7-54 reprograms M2-like fibrosis-inducing macrophages into fibrosis-suppressing macrophages, resulting in dramatic declines in profibrotic cytokine release, hydroxyproline biosynthesis, and collagen deposition, with concomitant increases in alveolar airspaces. Although nontargeted TLR7-54 is lethal at fibrosis-suppressing doses, FA-TLR7-54 halts fibrosis without evidence of toxicity. Taken together, FA-TLR7-54 is shown to constitute a novel and potent approach for treating fibrosis without causing dose-limiting systemic toxicities.
Insights
A novel folate-targeted therapy, FA-TLR7-54, effectively suppresses fibrosis by reprogramming macrophages. This approach halts fibrotic disease progression without the systemic toxicity associated with traditional treatments.
Area of Science:
- Immunology
- Pharmacology
- Pathology
Background:
- Fibrotic diseases are a major cause of organ failure and mortality in the US.
- Activated macrophages drive fibrosis by releasing cytokines that stimulate fibroblast collagen production.
- Current therapies targeting macrophage cytokines, like TLR7 agonists, exhibit systemic toxicity.
Purpose of the Study:
- To develop a targeted therapy for fibrosis by leveraging folate receptor β expression on activated myeloid cells.
- To evaluate the efficacy and safety of a novel folate-targeted TLR7 agonist (FA-TLR7-54) in suppressing fibrosis.
Main Methods:
- Creation of FA-TLR7-54, a folate-targeted TLR7 agonist.
- Administration of FA-TLR7-54 to models of fibrotic disease.
- Assessment of macrophage reprogramming, cytokine production, collagen deposition, and lung function.
Main Results:
- FA-TLR7-54 selectively accumulated in profibrotic macrophages.
- The targeted agonist reprogrammed M2 macrophages, reducing fibrosis-inducing cytokine release.
- FA-TLR7-54 significantly decreased collagen deposition and hydroxyproline biosynthesis.
- Treatment halted fibrosis without dose-limiting systemic toxicity, unlike non-targeted TLR7-54.
Conclusions:
- FA-TLR7-54 represents a potent and novel therapeutic strategy for treating fibrotic diseases.
- Targeted delivery overcomes the systemic toxicity limitations of previous TLR7 agonist approaches.
- This therapy offers a promising new avenue for managing organ failure caused by fibrosis.
